1. Field of the Invention
The present invention relates to percutaneous sorbefacients for electroporation which are suitable for enhancing an efficiency of administrating drugs by electroporation and to compositions for electroporation comprising the same. The present invention is useful in the field of drugs.
2. Description of the Related Art
Although percutaneous absorption route has been expected as an administration route for drugs, since it gives less pain than injection does and also involves less possibility of forgetting to administrate drugs than oral administration does, it is considerably difficult to allow percutaneous absorption due to a preventive function that the skin inherently has. Under the present circumstances, however, the percutaneous absorption route has not been established yet as means for delivering drugs. As one devised method to overcome the present problem, a so-called electroporation may be exemplified according to which pores are formed in the skin structure by application of a voltage and a drug is delivered through these pores. Recently, it has become clearer that in such an electroporation, the behavior of drugs is different from that in ordinary administration so that it has been desired to develop compositions for percutaneous administration which are suitable for such an electroporation. Also, it has been desired to develop percutaneous sorbefacients having an effect of promoting percutaneous absorption of drugs under such an electroporation. Under the present circumstances, however, these have not been obtained yet.
Meanwhile, since monoterpenes such as menthol used as general-purpose materials in the field of skin external agents have not been used in electroporation, it has been unknown at all that they have excellent percutaneous sorbefacients effects in electroporation.
Under the aforementioned circumstances, the present invention has been made and is aimed at providing a percutaneous sorbefacients in electroporation and a composition for percutaneous administration which is suitable for electroporation comprising the same.
In consideration of such circumstances, the present inventors have made extensive studies with efforts in pursuit of a composition for electroporation having excellent percutaneous absorption effects. As a result, the inventors have found that monoterpenes such as menthol exhibit excellent percutaneous sorbefacient effects under electroporation and that incorporation of monoterpenes in compositions for electroporation can give rise to compositions for electroporation having excellent percutaneous sorbefacient effects, thereby achieving the present invention. That is, the present invention provides a percutaneous sorbefacient for electroporation consisting of monoterpene and compositions for electroporation comprising the same.
(1) Percutaneous sorbefacient for electroporation of the present invention
The percutaneous sorbefacient for electroporation of the present invention consisits of monoterpene. Preferred examples of the monoterpene include menthol and optical isomers thereof, menthone, thymol, geraniol, pinene, citral, citronellal, etc. Of those, menthol is preferred and 1-menthol is more preferred. This is because menthols in particular 1-menthol have excellent percutaneous sorbefacient effects in electroporation. There are some monoterpenes that exhibit percutaneous sorbefacient effects in ordinary percutaneous administration where no electric field is applied. In such a case, the percutaneous sorbefacient effect is only a few times larger than that of a case where no monoterpene exists. In contrast, the percutaneous sorbefacient effect of the monoterpenes under electroporation according to the present invention is from several tens to several hundreds of times larger than that of a case where neither electric field is applied to nor monoterpene is added. Thus, there is exhibited a percutaneous sorbefacient effect enhanced to such an extent as is by no means expectable from the conventionally known percutaneous sorbefacient effect. In the compositions for electroporation of the present invention, a preferred content of the monoterpenes, which are percutaneous sorbefacients of the present invention is 0.1 to 10% by weight, more preferably 0.5 to 5% by weight. This is because if the monoterpenes are too much, they cause irritation in some cases and if they are too little, no percutaneous sorbefacient effect can be obtained in some cases.
(2) Compositions for electroporation of the present invention
The composition for electroporation of the present invention comprises the aforementioned percutaneous sorbefacient for electroporation. The compositions for electroporation of the present invention may comprise besides the monoterpenes (the percutaneous sorbefacients of the present invention), which are essential components, optional components for manufacturing pharmaceutical preparations used in ordinary composition for electroporation. Preferred examples of such optional components include hydrocarbons such as squalene, vaseline, microcrystalline wax, esters such as jojoba oil, carnauba wax, and octyldodecyl oleic acid, triglycerides such as olive oil, beef tallow, and coconut oil, fatty acids such as stearic acid, oleic acid and ricinoleic acid, higher alcohols such as oleyl alcohol, stearyl alcohol, and octyldodecanol, anionic surfactants such as sulfosuccinic acid esters and sodium polyoxyethylenealkylsulfates, amphoteric surfactants such as alkylbetaine salts, cationic surfactants such as dialkylammonium salts, nonionic surfactants such as sorbitan fatty acid esters, fatty acid monoglycerides, polyoxyethylene adducts of these, polyoxyethylene alkyl ethers and polyoxyethylene fatty acid esters, viscosity bodying and gelling agents, antioxidants, ultraviolet absorbents, coloring agents, preservatives, powders and the like. Further, as drugs that are percutaneously administered by such an electroporation, those usually used as medical preparations can be applied without any particular limitation. Preferred examples of such drags include analgesic antipyretic anti-inflammatory agents such as codeine, morphine, hydromorphone, oxycodone, pethidine, buprenorphin hydrochloride, pentazocine, and tramadol hydrochloride, protein-based drugs such as insulin, carcitonine, elcatonin, adrenocorticotrophic hormone (ACTH), parathyroid hormone (PTH), selectin, oxytocin, angiotensin, xcex2-endorphin, vasopressin, glucagon, somatostatin, luteinizing hormone-releasing hormone (LH-RH), enkephalin, neurotensin, atrial sodium diuretic peptide (ANP), growth hormone, bradykinin, substance P, dynorphin, thyroid stimulating hormone (TSH), prolactin, G-CSF, glutathione peroxidase, super-oxide dismutase (SOD), desmopressin, somatomedin, melanocyte stimulating hormone (MSH), calcitonin gene related peptide (CGRP), endothelin, and thyrotropin releasing hormone (TRH), interleukins, interferons, anti-platelet drugs, vasodilaters, argatroban as anti-arteriosclerotic drug, salpogrelate hydrochloride, sodium beraprost, limaprost alfadex, and cilostazol and the like. These drugs should be administered with passage of time by necessary amounts so that they are agreeable to the properties of percutaneous administration. The compositions for electroporation of the present invention are processed into preparations forms in conformity with the physical properties of the active ingredients, such as solutions, emulsions, semi-solids, and solids, by treating the aforementioned essential components, preferred components, optional components and active ingredients, and are used in electroporation. That is, by using the compositions of the present invention, drugs as active ingredients can be percutaneously administered by electroporation. Upon electroporation, they are used together with a device for electroporation. Among the aforementioned preparation forms, preferred one includes aqueous preparation forms and particularly preferred are an aqueous solution preparation form, aqueous gel preparation form and emulsion preparation form.
(3) Unit for administrating a drug for external application to the skin
The unit for administrating drugs for external application to the skin of the present invention includes the composition for electroporation and a device for electroporation of the present invention in combination. The device for electroporation is not particularly limited as far as it is used usually in such a use, and for example, those devices described in Japanese Domestic Patent Laid Open Publication No. Hei 11-507341(laying open of a Japanese translation), Japanese Domestic Patent Laid open Publication No. Hei 11-505445(laying open of a Japanese translation), Japanese Domestic Patent Laid Open Publication No. Hei 10-502827(laying open of a Japanese translation), Japanese Domestic Patent Laid Open Publication No. Hei 11-503349(laying open of a Japanese translation), Japanese Domestic Patent Laid Open Publication No. Hei 08-511680(laying open of a Japanese translation), Japanese Domestic Patent Laid Open Publication No. Hei 03-502416(laying open of a Japanese translation), etc. may be used. Further, those commercially available devices for such an electroporation include ECM-600 produced by BTX Co., GENE PULSER produced by BIO-RAD Co., etc. Also, these may be used. As for the conditions of electroporation, it is preferred to impress electric current for about 30 seconds with the voltage set to about 300 V and the capacitance of capacitor set to about 25 RF.